This K99/R00 career development award proposal (Intersection of Pain and Ethanol-Seeking Mechanisms in Ethanol Dependence) incorporates themes related to neuronal mechanisms I have investigated in the past, including the regulation of in vivo intracellular signaling and compulsive drug taking and drug-seeking behaviors, using models of drug dependence in rats. These studies were conducted with the support of individual NRSA awards at both pre- and postdoctoral levels. The aim of this proposal is to incorporate new training in neurochemistry (in vivo microdialysis) and nociceptive behavioral techniques, and to integrate the use of a comparative species (mice), to complement and enrich this background. I feel that this combination of new techniques (learned during the K99 phase) applied to the investigation of pain and ethanol-seeking behaviors will provide valuable insight into alcohol dependence, and, when combined with the personalized mentoring provided by Drs. Parsons and Koob within an environment as rich as The Scripps Research Institute, will greatly facilitate my transition to an independent research career during the R00 phase. The research development plan is conducted in accordance with the TSRI postdoctoral office's Individual Development Plan (IDP) program, and includes specialized training elements serving both immediate and long-term goals related to such topics as grantsmanship, effective scientific communication, and ethics. The main research objective of the current proposal is to investigate the convergence of central nociceptive and ethanol-seeking biobehavioral mechanisms in promoting and/or maintaining the ethanol-dependent state. Based on previous data from both pain- and ethanol-related fields, I hypothesize a specific role for increased endogenous cannabinoid activity and associated MAP kinase signaling potentiation in the anterior cingulate cortex in mediating this intersection, and further hypothesize that chronic pain states facilitate the transition from ethanol use to dependence via this mechanism. I propose an innovative experimental strategy that combines highly relevant behavioral techniques with comparative in vivo measures of neurotransmitter levels and intracellular signaling spanning from the extracellular space to the nucleus, including measures of both pre- and postsynaptic protein phosphorylation. Experiments conducted during the R00 phase will build on K99 phase work, and should provide a substantial base for my future investigations into the biobehavioral mechanisms of alcohol dependence. A better understanding of the relationship between chronic ethanol exposure, altered nociception, and compulsive ethanol seeking will provide further insight into mechanisms underlying the transition from recreational alcohol use to alcoholism, as well as reveal new treatment opportunities. PUBLIC HEALTH RELEVANCE: Individuals suffering from chronic pain may be more vulnerable to develop alcohol dependence and use alcohol to treat pain symptoms. This project will examine overlapping brain biochemical mechanisms of pain and alcoholism that contribute to the worsening and potential interdependence of these two disorders, with the ultimate goal of developing better therapeutic strategies for these devastating conditions.